Label-independent detection (LID) based optical readers can be used to detect drug binding to a target molecule such as a protein, or changes in living cells as material is displaced within a cell in response to a drug. Certain types of LID optical readers measure changes in refractive index on the surface of a resonant waveguide grating (RWG) biosensor for an array of RWG biosensors. The individual RWG biosensors are located in respective wells of a microplate. Spectrally broadband light from a light source is directed to each RWG biosensor. Only light whose wavelength is resonant with the RWG biosensor is strongly reflected. This reflected light is collected and spectrally analyzed to determine the resonant wavelength, with shifts in wavelength being representative of refractive index changes from biomolecular binding to the RWG biosensor, or similarly representing material displacements within cells immobilized to the sensor surface.
The repeatability of the resonant wavelength measurements depends on the precise positioning of the interrogation beam relative to the RWG sensor. This can require the optical reader to have an active positioning system for the microplate, which makes the reader expensive and complex. An alternative solution is to have a large interrogation beam that captures all of the information from the sensor. However, this results in problems distinguishing information from the “signal” biosensor from that of the “reference” biosensor.